TRPA1 antagonists

ABSTRACT

Compounds of formula (I) 
                         
wherein R 1 , R 2 , R 3 , m, and Y are defined in the specification are TRPA1 antagonists. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

This application claims priority to U.S. Ser. No. 61/019,021 filed Jan.4, 2008 and is incorporated herein by reference.

TECHNICAL FIELD

The present invention generally relates to TRPA1 antagonists,compositions comprising such compounds, and methods of treatingconditions and disorders using such compounds and compositions.

BACKGROUND

TRPA1 is a nonselective cation channel that belongs to the superfamilyof Transient Receptor Potential (TRP) ion channels. Like other familymembers, functional TRPA1 channels are formed by tetramerization of 4subunits, each containing six transmembrane domains, a pore loop betweentransmembrane domain 5 (S5) and 6 (S6), and intracellular N- andC-termini. TRPA1 is expressed in sensory neurons and co-localized withpain markers such as TRPV1, calcitonin gene-related peptide andbradykinin receptor (Nagata, K. et al., Journal of Neuroscience 2005,25, 4052-4061; Story, G. M. et al., Cell 2003, 112, 819-829; Corey, D.P. et al., Nature 2004, 432, 723-730; Bautista, D. M. et al.,Proceedings of the National Academy of Science U.S.A. 2005, 102,12248-12252; Jaquemar, D. et al., Journal of Biological Chemistry 1999,274, 7325-7333). In pain models, knockdown of TRPA1 expression by genespecific antisenses prevented and reversed cold hyperalgesia induced byinflammation and nerve injury (Obata, K. et al., Journal of ClinicalInvestigation 2005, 115, 2393-2401; Jordt, S. E. et al., Nature 2004,427, 260-265; Katsura, H. et al., Exploratory Neurology 2006, 200,112-123). Furthermore, TRPA1 gene knockout resulted in impaired sensoryfunctions and deficits in bradykinin-evoked pain hypersensitivity (Kwan,K. Y. et al. Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006,124, 1269-1282). Collectively, these data suggest that TRPA1 plays animportant role in sensory functions and pain states. As a ligand-gatedchannel, TRPA1 can be activated by a variety of stimuli, includingnoxious cold, intracellular Ca²⁺, endogenous substances (e.g.,bradykinin), pungent natural products (e.g., allyl isothiocyanate, orAITC), environmental irritants (e.g., acrolein), amphipathic molecules(e.g., trinitrophenol and chlorpromazine) and pharmacological agents(e.g., URB597) (Macpherson, L. J. et al., Current Biology 2005, 15,929-934; Bandell, M. et al., Neuron 2004, 41, 849-857). Bradykininactivates TRPA1 indirectly through the phospholipase C pathway followingbinding of bradykinin to its receptors. Trinitrophenol andchlorpromazine open TRPA1 by inducing curvature or crenation in thelipid bilayer membrane (Xu, H. et al., Nat. Neurosci. 2006, 9, 628-635;Hill, K. and Schaefer, M., J. Biol. Chem. 2007, 282, 7145-7153;Niforatos, W. et al., Molecular Pharmacology 2007, 71, 1209-1216). Mostrecently, it was shown that TRPA1 agonists could directly interact withthe channel protein. AITC and cinnamaldehyde covalently modify severalcysteine and lysine residues localized in the cytoplasmic N terminus andactivate the channel (Hinman, A., Chuang, H. H., Bautista, D. M., andJulius, D. Proceedings of the National Academy of Science U.S.A. 2006,103, 19564-19568; Macpherson, L. J., Dubin, A. E., Evans, M. J., Marr,F., Schultz, P. G., Cravatt, B. F., and Patapoutian, A., Nature 2007,445, 541-545). In addition, intracellular Ca²⁺ binds to the N-terminusEF-hand domains and mediates channel opening (Zurborg, S. et al., NatureNeuroscience 2007, 10, 277-279). Together these findings have revealedpotential physiological roles of TRPA1, and also indicate that TRPA1channel gating may involve different mechanisms and moleculardeterminants.

Thus, modulation of TRPA1 can have many industrial and therapeuticapplications. For example, TRPA1 antagonists may fulfill the need in theart for new analgesic pharmaceuticals suitable for the treatment and/orprophylaxis of nociceptive and neuropathic pain in mammals, especiallyin humans.

SUMMARY

Disclosed herein are methods for treating disorders that are amelioratedby inhibition of TRPA1. Such methods comprise of administering to thesubject a therapeutically effective amount of one or more TRPA1antagonists, alone, or in combination with one or more pharmaceuticallyacceptable carriers. The TRPA1 antagonists employed are selected fromcompounds of formula (I), or solvates, pharmaceutical salts, prodrugs,salts of prodrugs, or any combinations thereof,

wherein

R¹ represent optional substituents of the phenyl group and each R¹ isindependently alkyl, alkenyl, alkynyl, —CN, halogen, —OR^(a), —NO₂,—N(R^(a))(R^(b)), —N(R^(b))C(O)R^(a), —N(R^(b))S(O)₂R^(1a),—N(R^(b))C(O)OR^(a), —N(R^(b))C(O)N(R^(a))(R^(b)),—N(R^(b))S(O)₂N(R^(a))(R^(b)), —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))(R^(b)), —SR^(a), —SF₅, —S(O)R^(1a), —S(O)₂R^(1a),—S(O)₂OR^(1a), —S(O)₂N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—CN, haloalkyl,—(CR^(d)R^(e))_(q)—OR^(a), —(CR^(d)R^(e))_(q)—NO₂,—(CR^(d)R^(e))_(q)—N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂R^(1a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—C(O)R^(a), —(CR^(d)R^(e))_(q)—C(O)OR^(a),—(CR^(d)R^(e))_(q)—C(O)N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—S(O)₂R^(1a),—(CR^(d)R^(e))_(q)—S(O)₂OR^(1a), or—(CR^(d)R^(e))_(q)—S(O)₂N(R^(a))(R^(b));

R² is hydrogen, C₁₋₆ alkyl, or haloalkyl;

R³ is C₁₋₆ alkyl, haloalkyl, or cyclopropyl, wherein the cyclopropyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents as representedby R^(j);

R^(j), at each occurrence, is independently C₁₋₄ alkyl, halogen, orhaloalkyl;

Y is —OH, —O(C₁₋₄ alkyl), —N(R^(f))(R^(g)), —N(R^(f))C(O)R^(g),—N(R^(f))S(O)₂R^(g), or —N(R^(f))C(O)N(R^(f))(R^(g));

R^(a) and R^(b), at each occurrence, are each independently hydrogen,alkyl, or haloalkyl;

R^(1a), at each occurrence, is independently alkyl or haloalkyl;

R^(d) and R^(e), at each occurrence, are each independently hydrogen,alkyl, halogen, or haloalkyl;

R^(f) and R^(g), at each occurrence, are each independently hydrogen,alkyl, or haloalkyl;

m is 0, 1, 2, 3, 4, or 5; and

q is 1, 2, 3, or 4;

with the proviso that the TRPA1 antagonist is not(Z)-4-(4-chlorophenyl)-3-methylbut-3-en-2-oxime or(E)-4-(4-chlorophenyl)-3-methylbut-3-en-2-oxime.

Some of the methods are directed to treating subjects suffering fromacute cerebral ischemia, chronic pain, neuropathic pain, inflammatorypain, post herpetic neuralgia, neuropathies, neuralgia, diabeticneuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthriticpain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain,dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia,neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrualpain; bladder disease such as incontinence, micturition disorder, renalcolic and cystitis; inflammation such as burns, rheumatoid arthritis andosteoarthritis; neurodegenerative disease such as stroke, post strokepain and multiple sclerosis; pulmonary disease such as asthma, cough,chronic obstructive pulmonary disease (COPD) and broncho constriction;gastrointestinal disease such as gastroesophageal reflux disease (GERD),dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD), colitis and Crohn's disease; and ischemia such ascerebrovascular ischemia; emesis such as cancer chemotherapy-inducedemesis, or obesity. In some methods, the subject being treated is human.In some methods, one or more second pain reducing agents can beco-administered with the TRPA1 antagonist(s) as set forth above, aloneor with one or more pharmaceutically acceptable carrier(s).

A further aspect of the invention provides a use of TRPA1 antagonists,alone or in combination with one or more second pain reducing agent, inthe manufacture of a medicament for treating conditions and disordersdisclosed herein.

For example, the second pain reducing agent can be an analgesic agentselected from acetaminophen, or a nonsteroidal anti-inflammatory drug(NSAID), or combinations thereof. In some embodiments, the nonsteroidalanti-inflammatory drug is ibuprofen. The second pain reducing agent canalso be opioids.

Pharmaceutical compositions comprising one or more compound of formula(I), or pharmaceutically acceptable salts thereof, alone, or incombination with one or more second pain reducing agents, are alsoprovided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1—depicts the effect of Example 1 on hindlimb grip force inosteoarthritic rats.

DETAILED DESCRIPTION

Compounds of formula (I) are disclosed in this invention,

wherein R¹, R², R³, Y, and m are defined above in the Summary of theInvention and below in the Detailed Description. Further, compositionscomprising such compounds and methods for treating conditions anddisorders using such compounds and compositions are also disclosed.

Compounds disclosed herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

a. Definition

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond. Representative examples of alkenyl include,but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and3-decenyl.

The term “alkyl” as used herein, means a straight or branched saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “C₁₋₆alkyl” means a straight or branched saturated hydrocarbon chaincontaining from 1 to 6 carbon atoms. The term “C₁₋₄ alkyl” means astraight or branched saturated hydrocarbon chain containing from 1 to 4carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, 4,4,4-trifluorobutyl, and 2-chloro-3-fluoropentyl.

The term “subject” includes mammals, especially humans, as well as othernon-human animals, e.g. horses, dogs, cats, and fish.

b. Compounds

Compounds of the invention have the general formula (I) as describedabove.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In compounds of formula (I), R² is hydrogen, C₁₋₆ alkyl, or haloalkyl.For example, R² is C₁₋₆ alkyl such as, but not limited to, methyl. Insome embodiments, R² is hydrogen.

R³ is C₁₋₆ alkyl, haloalkyl, or optionally substituted cycloalkyl. Forexample, R³ is C₁₋₆ alkyl such as, but not limited to, methyl, ethyl,n-propyl, tert-butyl, n-butyl, and isopropyl.

R¹ is an optional substituent of the phenyl group in formula (I) asdescribed in the Summary. In certain embodiments, R¹ is halogen, alkyl(for example, C₁₋₄ alkyl such as, but not limited thereto, methyl),haloalkyl (e.g. trifluoromethyl), or —CN.

Y is —OH, —O(C₁₋₄ alkyl), —N(R^(f))(R^(g)), —N(R^(f))C(O)R^(g),—N(R^(f))S(O)₂R^(g), or —N(R^(f))C(O)N(R^(f))(R^(g)); wherein R^(f) andR^(g) are as described in the Summary. In certain embodiments Y is —OHor —O(C₁₋₄ alkyl), for example, Y is —OH or —O(methyl). Certainembodiments of invention include compounds of formula (I) wherein Y is—N(R^(f))(R^(g)), —N(R^(f))C(O)R^(g), —N(R^(f))S(O)₂R^(g), or—N(R^(f))C(O)N(R^(f))(R^(g)); and R^(f) and R^(g) are as described inthe Summary.

It is appreciated that the present invention contemplates methods fortreating conditions and disorders described herein using compounds offormula (I), pharmaceutically acceptable salts, prodrugs, salts ofprodrugs, solvates, or any combinations thereof, with combinations ofthe above embodiments, including particular, more particular andpreferred embodiments.

Accordingly, examples of a group of compounds of formula (I) include,but are not limited to, those wherein R² is C₁₋₆ alkyl, R³ is C₁₋₆alkyl, and m, R¹, and Y are as disclosed in the Summary. For example, R²is methyl. R³, for example, include ethyl, n-propyl, tert-butyl,n-butyl, and isopropyl.

Other examples of a group of compounds of formula (I) include, but arenot limited to, those wherein R² is hydrogen, R³ is C₁₋₆ alkyl, and m,R¹, and Y are as disclosed in the Summary. R³, for example, includeethyl, n-propyl, tert-butyl, n-butyl, and isopropyl.

Within the two groups of compounds of formula (I) as described hereinabove, examples of a subgroup include those wherein Y is —OH.

Other examples of a subgroup include, but are not limited to, thosewherein Y is O(C₁₋₄ alkyl), for example, Y is —O(methyl).

Examples of yet another subgroup of compounds of formula (I) includethose wherein Y is —N(R^(f))(R^(g)), —N(R^(f))C(O)R^(g),—N(R^(f))S(O)₂R^(g), or —N(R^(f))C(O)N(R^(f))(R^(g)); and R^(f) andR^(g) are as described in the Summary.

Of all the groups and subgroups of compounds of formula (I) disclosed inthe preceding paragraphs, R¹ and m are as described in the Summary. Forexample, R¹ is halogen, alkyl (for example, C₁₋₄ alkyl such as, but notlimited thereto, methyl), haloalkyl (e.g. trifluoromethyl), or —CN. Inone embodiment, m is 0. In other embodiment, m is 1, 2, or 3.

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. The present invention contemplates various individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of the present inventionmay be prepared synthetically from commercially available startingmaterials that contain asymmetric or chiral centers or by preparation ofracemic mixtures followed by resolution of the individual stereoisomerusing methods that are known to those of ordinary skill in the art.Examples of resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

The invention also contemplates the various geometric isomers andmixtures thereof resulting from the disposition of substituents around acarbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkylgroup, or a heterocycle group. Substituents around a carbon-carbondouble bond or a carbon-nitrogen double bond are designated as being ofZ or E configuration and substituents around a cycloalkyl or heterocycleare designated as being of cis or trans configuration.

Examples of some of the possible geometrical isomers of compounds offormula (I) include, but are not limited to, (Ia), (Ib), (Ic), and (Id).

wherein R¹, m, R², R³, and Y have meanings as described in the Summaryand the Detailed Description. It is understood that embodiments for R¹,R², Y, m, and R³, and combinations of embodiments, including particular,and more particular embodiments as described for formula (I), are alsocontemplated for compounds of formula (Ia), (Ib), (Ic), and (Id).

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formulae drawings.

Exemplary TRPA1 antagonists to be employed for the treatment ofconditions and disorders described herein include, but are not limitedto:

-   (1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one O-methyloxime;-   (1E,3E)-1-(2-fluorophenyl)-2-methylpent-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)-2-methylhex-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)-2,4,4-trimethylpent-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)-2-methylhept-1-en-3-one oxime;-   (1E,3Z)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime;-   (1E,3E)-1-(3-chloro-4-fluorophenyl)-2-methylpent-1-en-3-one oxime;-   (1E,3Z)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one oxime;-   (2E,3E)-4-(4-fluorophenyl)but-3-en-2-one oxime;-   (1E,3E)-1-(4-fluorophenyl)hex-1-en-3-one oxime;-   (1E,3E)-1-(4-fluorophenyl)pent-1-en-3-one oxime;-   (1E,3Z)-1-(4-fluorophenyl)pent-1-en-3-one oxime;-   (1E,3E)-1-(3,4-difluorophenyl)-2-methylpent-1-en-3-one oxime; and-   (1E,3E)-2-methyl-1-(3,4,5-trifluorophenyl)pent-1-en-3-one oxime;    or pharmaceutically acceptable salts, prodrugs, salts of prodrugs,    solvates, or combinations thereof.

c. Biological Data

(i) In Vitro Data—Determination of Inhibition Potencies

Molecular biology and transient expression were performed as describedin Chen, J. et al., Journal of Biomolecular Screening 2007, 12, 61-69.Briefly, TRPA1 full length cDNA was amplified from human dorsal rootganglia total RNA (BD Bioscience Clontech, Palo Alto, Calif., USA) andwas cloned into pcDNA3.1/V5-His Topo vector (Invitrogen, Carlsbad,Calif.). Large scale transient transfection was performed using theFreeStyle™ 293 Expression System as recommended by the manufacturer(Invitrogen). HEK293-F cells were grown in suspension in flasks (cellvolume 30 mL to 1 liter) or in a Wave Bioreactor (Wave Biotech,Somerset, N.J.) (6 liters). To support high density, suspension cultureand transfection, cells were cultured in FreeStyle 293 media, anoptimized, serum free formulation. 293fectin™ (Invitrogen) was used astransfection reagent. In a transfection of 3×10⁷ cells (30 mL volume),30 μg of plasmid DNA and 40 μL 293 fectin were used. For a larger volumetransfection, each reagent was scaled up proportionally. Two dayspost-transfection, cells were harvested by centrifugation (1000×g, 5minutes) and resuspended to a density of 1.5×10⁷ cells/mL in freezingmedium (Freestyle media/10% serum/10% DMSO). Cells were transferred intocryovials in 2 mL aliquots, and these vials were placed in Nalgene Mr.Frosty slow-freeze devices (Sigma-Aldrich, St. Louis, Mo.) at −80° C. Asneeded, vials were removed from −80° C. and quickly thawed in a 37° C.water bath. Cells were aseptically transferred into conical tubescontaining Freestyle media (10 mL/vial). After centrifugation at 1,000×gfor 3-5 minutes, medium was removed by aspiration and cells wereresuspended in Freestyle medium at desired densities (typically 1×10⁶cells/mL). Re-suspended cells were seeded into black-walled clear-bottom96-well Biocoat™ poly-D-lysine assay plates (BD Biosciences, Bedford,Mass.)(10⁵ cells/well) and incubated overnight at 37° C. under ahumidified 5% CO₂ atmosphere.

FLIPR Based Intracellular Ca²⁺ Assay and Membrane Potential Assay

Ca²⁺ influx was measured using a FLIPR calcium assay kit (R8033;Molecular Devices, Sunnyvale, Calif.). The Ca²⁺ indicator dye wasdissolved in Hanks' balanced salt solution supplemented with 20 mM HEPESbuffer (HBSS/HEPES) according to the manufacturer instructions. Prior tostart of the assay, the medium was removed by aspiration, and cells wereloaded with 100 μL Ca²⁺ dye for 2 to 3 hours at room temperature. AITC(allyl isothiocyanate) was used to activate and open the channels. (4×)solutions of the test compounds were prepared in HBSS/HEPES, and 50 μLwere added to the cells at a delivery rate of 10 μL/sec. Changes influorescence were measured over time in a fluorometric imaging platereader (FLIPR, Molecular Devices). Two additions were made over thecourse of an experimental run. For agonist experiments, assay buffer wasadded at the 10 s time point, followed by addition of agonist at the 3minute 10 sec time point. For antagonist experiments, the antagonist wasadded at the 10 sec time point, followed by addition of the agonist 3minutes later. Final assay volume for both the agonist and antagonistexperiments was 200 μL. Total length of an experimental run was 6.5minutes.

Data was analyzed with GraphPad Prism® software (GraphPad Software, SanDiego, Calif.), using a four-parameter logistic Hill equation tocurve-fit concentration-effect data and derive EC₅₀ or IC₅₀ values.Numerical values are reported as mean±SEM (n=number of experiments). SEMis calculated by dividing the standard deviation by the square root ofthe sample size (minus 1).

Changes in membrane potential were measured in hTRPA1-expressing LSTTcells using a FLIPR membrane potential assay kit (R8034, MolecularDevices). The procedure for thawing and plating the LSTT cells wasidentical to the Ca²⁺ influx assay (see above). The membrane potentialdye was dissolved in HBSS/HEPES buffer according to the manufacturer'sinstructions, and then cells were loaded with dye (100 μL/well) for 45minutes to 2 hours at room temperature. The protocol for addition ofchemical agents, and measurement of changes in fluorescence, was thesame as the Ca²⁺ influx assay, except for the emission filter setting.The results are shown in Table 1.

TABLE 1 Human TRPA1 Example IC₅₀ (μM) 1 0.074 2 8.3 3 4.6 4 0.50 5 8.0 64.4 7 0.85 8 3.3 9 6.0 10 0.701 11 20.6 12 5.91 13 9.46 14 0.574 15 4.6716 >100 17 >100 18 >100 19 >100

Certain compounds of the invention were tested in the assay describedabove and are effective TRPA1 antagonists with IC₅₀ values from about 25μM to about 100 nM, for example, from about 5 μM to about 80 nM.

(ii) Pharmacokinetic Data

Groups of three fasted male Sprague-Dawley rats received a 10 μmol/kg (2m/kg) oral dose of the test compound, administered by gavage. Thecompounds were prepared as a solution in a 10% DMSO/poly(ethyleneglycol)-400 (v/v). Blood samples were obtained from each animal atvarious time points up to eight hours after dosing.

Test compound was selectively extracted from plasma and brain homogenateusing liquid-liquid extraction with tert-butylmethylether. The compoundsof interest were separated from co-extracted contaminants on a 50×3 mm,Luna CN column (Phenomenex), with an acetonitrile:0.1% aqueoustrifluoroacetic acid mobile phase at a flow rate of 0.35 ml/min. Plasmaconcentrations were determined by HPLC-MS/MS on an API2000 with TurboIon Spray interface, with MRM detection in the positive ionization mode.To calibrate compound concentration, a separate portion of each tissuesample was spiked with a known quantity of test compound and analyzedsimultaneously with the samples. The results are shown in Table 2.

TABLE 2

R³ = CH₃ R³ = CH₂CH₃ (Compound A) (Example 1) Human TRPA1 0.33 0.074IC₅₀ (μM) F, rat (oral 4% 38% bioavailability) @ 10 μmol/kg Cmax (μM)0.22 0.72 @ 10 μmol/kg plasma/brain 0 1.2

As shown in Table 2, Example 1 exhibited better potency in theinhibition of TRPA1 and better bioavailability than Compound A. CNSpenetration of Example 1 is also superior to Compound A, as demonstratedby the brain/plasma ratio after oral administration. These resultssuggest that compounds of the invention are of value as bettertherapeutic agents for the treatment of pain, particularly in painmediated by central sensitization such as chronic inflammatory pain andosteoarthritic pain.

(iii) In Vivo Data—Effects on Grip Force in Osteoarthritic Rats

Unilateral knee joint osteoarthritis was induced in the rats by a singleintra-articular (i.a.) injection of sodium monoiodoacetate (MIA) (Sigma,St. Louis, Mo.) (3 mg in 0.05 mL sterile isotonic saline) into the jointcavity using a 26G needle under light (2-4%) halothane (HalocarbonLaboratories, River Edge, N.J.) anesthesia. Following injection, theanimals were allowed to recover from the effects of anesthesia (usually5-10 minutes) before returning them to their home cages. Animals weretested 21 days after MIA injection. Measurements of peak hind limb gripforce were conducted by recording the maximum compressive force exertedon the hind limb strain gauge setup, in a commercially available gripforce

FIG. 1—depicts the effect of Example 1 on hindlimb grip force inosteoarthritic rats measurement system (Columbus Instruments, Columbus,Ohio). In this experiment, ED₅₀ was 112 μmol/kg p.o. (95% CI, 79-158μmol/kg). During testing, each rat was gently restrained by graspingaround its rib cage and then allowed to grasp the wire mesh frame (10-12cm²) attached to the strain gauge. The experimenter then moved theanimal in a rostral-to-caudal direction until the grip was broken. Eachrat was sequentially tested twice at approximately 2-minute interval toobtain a raw mean grip force (CFmax). This raw mean grip force data wasin turn converted to a maximum hind limb compressive force (CFmax) (gramforce) per kg body weight for each animal. A group of age matched naïveanimals was added to each experiment and the data obtained from thedifferent dose groups for the compound being tested were compared to thenaïve group. Example 1 is fully efficacious in this model with an ED₅₀of 112 μmol/kg. Example 1 exhibits excellent plasma and brain exposurewith increasing oral dose. At the 100 μmol/kg dose in the osteoarthritisgrip force model, the measured plasma concentration of Example 1 was 6.2μM.

d. Methods of Using the Compounds

Compounds described herein are TRPA1 antagonist and are capable ofinterfering with the expression, modification, regulation, or activationof TRPA1, or down-regulates one or more of the normal biologicalactivities of TRPA1 (e.g. its ion-channel).

One embodiment of the present invention provides a method for treating adisorder that may be ameliorated by inhibiting TRPA1 receptor in asubject in need of such treatment. The method comprises administering atherapeutically effective amount of one or more compounds of formula(I), solvates, pharmaceutically acceptable salts, prodrugs, salts ofprodrugs, or any combination thereof, or any combination thereof, aloneor in combination with one or more pharmaceutically acceptable carriers.

Another embodiment of the present invention provides a method fortreating pain (e.g. nociceptive pain, neuropathic pain, inflammatorypain, osteoarthritic pain, etc.) in a subject in need of such treatment.This method comprises administering a therapeutically effective amountof one or more compounds of formula (I), solvates, pharmaceuticallyacceptable salts, prodrugs, salts of prodrugs, or any combinationthereof, or any combination thereof, alone or in combination with one ormore pharmaceutically acceptable carriers.

Yet another embodiment of the present invention provides a method forprophylaxis or treatment of ischemia including acute cerebral ischemia,pain including chronic pain, neuropathic pain, nociceptive pain,allodynia, inflammatory pain, inflammatory hyperalgesia, post herpeticneuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-relatedneuropathy, nerve injury, rheumatoid arthritic pain, osteoarthriticpain, burns, back pain, visceral pain, cancer pain, dental pain,headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis,sciatica, pelvic hypersensitivity, pelvic pain, and menstrual pain;bladder disease such as incontinence and bladder overactivity, bladdercystitis, micturition disorder, and renal colic; inflammation such asburns, oral mucositis, rheumatoid arthritis and osteoarthritis;neurodegenerative disease such as stroke, post stroke pain and multiplesclerosis; pulmonary disease such as asthma, cough, chronic obstructivepulmonary disease (COPD) and bronchoconstriction; skin disorders such aspsoriasis, eczema, and dermatitis; gastrointestinal disease such asgastroesophageal reflux disease (GERD), dysphagia, ulcer, irritablebowel syndrome (IBS), inflammatory bowel disease (IBD), colitis andCrohn's disease; ischemia such as cerebrovascular ischemia; emesis suchas cancer chemotherapy-induced emesis, in mammals, especially humans.For example, the compounds of formula (I) are useful for the treatmentof pain, particularly nociceptive and inflammatory pain, moreparticularly, osteoarthritic pain. This method comprises the step ofadministering to a subject in need thereof a therapeutically effectiveamount of one or more compounds of formula (I), solvates,pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or anycombination thereof, alone or in combination with one or morepharmaceutically acceptable carriers.

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used forprophylaxis or treatment of inflammatory, nociceptive, and neuropathicpain as demonstrated by Bautista, D. Cell 2006, 124, 1269-1282;Trevisani, M. et al. Proceedings of the National Academy of Sciences USA2007, 104, 13519-13524; Dai, Y. et al. Journal of Clinical Investigation2007, 117, 1979-1987; Diogenes, A. et al. Journal of Dental Research2007, 86, 550-555; Katsura, H. et al. Journal of Neurochemistry 2007,102, 1614-1624; and McMahon, S. B. et al. Cell 2006, 124, 1123-1125.

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used forprophylaxis or treatment of colitis and Crohn's disease as demonstratedby Kimball, E. S. et al. Neurogastroenterology & Motility 2007, 19,90-400.

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used forprophylaxis or treatment of respiratory hypersensitivity such as cough,asthma, chronic obstructive pulmonary disease (COPD) (Andre et al.,Journal of Clinical Investigation 2008, 118, 2574-2582; Bessac et al.,Journal of Clinical Investigation 2008, 118, 1899-1910; Simon andLiedtke, Journal of Clinical Investigation 2008, 118, 2383-2386).

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used forprophylaxis or treatment of gastrointestinal diseases such as irritablebowel syndrome (IBS) and inflammatory bowel disease (IBD) asdemonstrated by Penuelas, A. et al. European Journal of Pharmacology2007, 576, 143-150 and Hayashi, S. et al. Inflammopharmacology 2007, 15,218-222.

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used forprophylaxis or treatment of cold hyperalgesia or cold sensitivity asdemonstrated by Story, G. M. Current Neuropharmacology 2006, 4, 183-196and Story, G. M. and Gereau, R. W. Neuron 2006, 50, 177-180.

Compounds of formula (I), including but not limited to those specifiedin the examples, solvates, pharmaceutically acceptable salts, prodrugs,salts of prodrugs, or any combination thereof, can be used as depilatoryagents to prevent or reverse hirsutism as demonstrated by Kwan, K. Y. etal. Neuron 2006, 50, 277-289.

Compounds described herein may be administered alone, or in combinationwith one or more other compounds of formula (I), or in combination (i.e.co-administered) with one or more additional pharmaceutical agents suchas a second pain reducing agent. For example, the second pain reducingagent can be an analgesic agent such as, but not limited to,acetaminophen, or a nonsteroidal anti-inflammatory drug (NSAID), orcombination thereof. Examples of nonsteroidal anti-inflammatory drug(NSAID) include, but not limited to, aspirin, diclofenac, diflusinal,etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen,olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine,sulindac, tolmetin and zomepirac. Yet other class of secondpain-reducing agent includes opioids. Other analgesic such as localanesthetics including anticonvulsants and antidepressants may also beused in the combination therapy. Administering one or more classes ofdrugs in addition to TRPA1 antagonists can provide more effectiveamelioration of pain. Combination therapy includes administration of asingle pharmaceutical dosage formulation containing one or more of thecompounds of formula (I) and one or more additional pharmaceuticalagents; as well as administration of the compounds of formula (I) andeach additional pharmaceutical agent, in its own separate pharmaceuticaldosage formulation. For example, one or more compounds of formula (I)and one or more additional pharmaceutical agents, may be administered tothe patient together, in a single oral dosage composition having a fixedratio of each active ingredient, such as a tablet or capsule; or eachagent may be administered in separate oral dosage formulations.

Where separate dosage formulations are used, each active ingredient maybe administered at essentially the same time (e.g., concurrently) or atseparately staggered times (e.g., sequentially).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

TRPA1 antagonists described herein can be administered alone, or as apharmaceutical composition comprising a therapeutically effective amountof one or more of the TRPA1 antagonists in combination with one or morepharmaceutically acceptable carriers, with or without one or more secondpain reducing agent. The phrase “therapeutically effective amount” meansa sufficient amount of TRPA1 antagonist to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

The total daily dose of the compounds of formula (I) administered to ahuman or lower animal range from about 0.10 μg/kg body weight to about50 mg/kg body weight. More preferable doses can be in the range of fromabout 0.10 μg/kg body weight to about 10 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

e. Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions thatcomprise TRPA1 antagonists of the present invention thereof. Thepharmaceutical compositions comprise compounds of formula (I), solvates,pharmaceutically acceptable salts, prodrugs, salts of prodrugs, orcombinations thereof that may be formulated together with one or morepharmaceutically acceptable carriers.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising one or more compounds of formula (I), solvates,pharmaceutically acceptable salts, prodrugs, salts of prodrugs, orcombinations thereof, and one or more pharmaceutically acceptablecarriers, in combination with one or more second pain reducing agents.In certain embodiments, the second pain reducing agent is an analgesicsuch as acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), orcombination thereof. In certain embodiments, the nonsteroidalanti-inflammatory drug is ibuprofen. In other embodiments, the secondpain reducing agent is an opioid. Other analgesics such as localanesthetics including anticonvulsants and antidepressants are alsocontemplated.

The pharmaceutical compositions of the invention can be used for thetreatment of the disorders as described herein in mammals, includinghuman.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form is accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts. The phrase “pharmaceuticallyacceptable salt” means those salts which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humansand lower animals without undue toxicity, irritation, allergic responseand the like and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq).

The compounds of the invention may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isothionate), lactate, malate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. General Synthesis

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds of the invention by metabolic processes include thoseoccurring in the human or animal body (in vivo) or processes occurringin vitro.

The synthesis of compounds of general formula (I) wherein the groups R¹,R², R³, R^(f), R^(g), m, and Y have the meanings as set forth in thesummary section unless otherwise noted, is exemplified in theaccompanying Schemes 1-5.

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: Dibal-H fordiisobutylaluminum hydride, DMAP for (4-dimethylamino)pyridine, DMF forN,N-dimethylformamide, DBU for 1,8-diazabicyclo(5.4.0)undec-7-ene, EDCIfor 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtfor 1-hydroxybenzotriazole, NMO for 4-methylmorpholine N-oxide, NMP forN-methylpyrrolidinone, PDC for pyridinium dichromate, PdCl₂(PPh₃)₂ forbis(triphenylphosphine)palladium(II) dichloride, Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium(0), Ph for phenyl, and TPAP fortetrapropylammonium perruthenate.

Compounds of general formula (I) wherein Y is —OH or —O(C₁₋₄ alkyl) canbe prepared using general procedures as illustrated in Scheme 1.

Benzaldehydes of general formula (1) can be reacted with phosphorusylides of general formula (2) wherein R″ is alkyl, in a solvent such astoluene at refluxing temperatures to provide unsaturated esters ofgeneral formula (3) (Adam, W. et al., Journal of Organic Chemistry 2002,67, 8395-8399). The conversion of compound (3) to (4) is a stepwisereaction sequence comprising: (a) reduction of (3) to the correspondingaldehyde using a reagent such as diisobutylaluminum hydride or lithiumaluminum hydride, (b) addition of an organometallic nucleophile in theform of a Grignard or organolithium reagent, and (c) conversion of theproduct from step (b) to the corresponding ketone derivative using anoxidizing reagent such as tetrapropylammonium perruthenate (Ley, S. V.et al. Synthesis 1994, 7, 639-966) or pyridinium dichromate (PDC). Step(b) can be carried out in a solvent such as tetrahydrofuran or diethylether at a temperature ranging from about −78° C. to about 0° C. Thecrude products from both steps (a) and (b) can be isolated and subjectedto the subsequent step with or without purification. Step (c) can becarried out using a variety of oxidizing agents known to those skilledin the art in non-polar solvents such as dichloromethane typically atambient temperatures. Condensation of ketone (4) with hydrochloride saltof hydroxylamine or alkoxyamine formula R^(x)ONH₂ wherein R^(x) ishydrogen or C₁₋₄ alkyl, in the presence of a base such as but notlimited to triethylamine in a solvent such as benzene or tetrahydrofuranat a temperature ranging from about 25° C. to about 80° C., providesoximes of general formula (5) or (6). Compounds (5) and (6) aregeometrical isomers which may be separated and purified by standardchromatographic methods familiar to those skilled in the art.

Alternatively, ketone (4) can be prepared employing general proceduresas illustrated in Scheme 2.

Unsaturated esters of general formula (3), prepared according to themethods of Scheme 1 or Scheme 3, can be reacted withN-methoxy-N-methylamine hydrochloride and trimethylaluminum (Lipton, M.F. et al. Organic Syntheses 1980, 59, 49-53) in a solvent such astoluene or dichloromethane at a temperature ranging from about −40° C.to about 25° C. to provide amides of general formula (7). Alternatively,(7) can be prepared by reacting (3) with N-methoxy-N-methylaminehydrochloride and isopropylmagnesium chloride (Williams, J. M. et al.Tetrahedron Letters 1995, 36, 5461-5464) in a solvent such astetrahydrofuran at a temperature ranging from about −20° C. to about 0°C.

Treatment of (7) with Grignard reagents of formula R³MgX¹⁰¹ wherein X¹⁰¹is Cl or Br, in a solvent such as tetrahydrofuran at a temperatureranging from about −78° C. to about 0° C. provides ketones of generalformula (4).

Intermediate (7) can also be prepared according to the syntheticsequence as shown in Scheme 3. Ester (3) can be saponified to carboxylicacid (8) using reagents such as lithium or potassium hydroxide inaqueous solution at ambient temperature using a co-solvents includingbut not limited to tetrahydrofuran and ethanol. Carboxylic acid (8) canbe reacted with N-methoxy-N-methylamine hydrochloride (Basha, A. et al.Tetrahedron Letters 1977, 48, 4171-4174), using dehydrative couplingreagents such as EDCI in combination with HOBt or DMAP (Montalbetti, C.A. G. N. Tetrahedron 2005, 61 10827-10852), and a base such as but notlimited to triethylamine. These reactions are carried out in a solventsuch as toluene or dichloromethane at a temperature ranging from about0° C. to about 25° C. to provide amides of general formula (7).

Alternatively, unsaturated esters of formula (3) may be preparedaccording to the procedures as described in Scheme 4.

Aryl halides of general formula (9) wherein the Z group is a chlorine,bromine, or iodine atom may be reacted with unsaturated esters offormula (10) in the presence of a palladium catalyst such as but notlimited to palladium(II) acetate to generate (3) (Knowles, J. P. Organic& Biomolecular Chemistry 2007, 5, 31-44). These reactions are generallyperformed using an amine base such as but not limited todiisopropylethylamine or DBU, in a solvent such as acetonitrile,toluene, or DMF at temperatures ranging from about 50° C. to about 100°C. A related approach for the synthesis of unsaturated esters of generalformula (3) from (9) involves reaction with substituted alkenes ofgeneral formula (11) wherein R′″ is alkyl. In this case, the substitutedalkene (11) contains a trialkyltin moiety such as trimethylstannyl ortributylstannyl (Yin, L. et al. Chemical Reviews 2007, 107, 133-173).These reactions are generally performed in the presence of catalyticquantities of a palladium(II) or palladium (0) reagent, such asdichloropalladium bis(triphenylphosphine) ortetrakis(triphenylphosphine)palladium, respectively, in polar aproticsolvents such as DMF or NMP at temperatures ranging from about 25° C. toabout 125° C.

Compounds of general formula (I) wherein Y is NR^(f)R^(g) can beprepared using general procedures as illustrated in Scheme 5.

Reaction of ketone (4), prepared according to the methods illustrated inSchemes 1 and 2 with substituted hydrazines of general formulaR^(f)R^(g)NNH₂ in a solvent such as benzene or tetrahydrofuran at atemperature ranging from about 0° C. to about 80° C. provides hydrazonesof general formula (12) or (13). Compounds (12) and (13) are geometricalisomers which may be separated and purified by standard chromatographicmethods familiar to those skilled in the art.

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be worked up in theconventional manner, e.g. by eliminating the solvent from the residueand further purified according to methodologies generally known in theart such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

Following Examples may be used for illustrative purposes and should notbe deemed to narrow the scope of the invention.

g. Examples Example 1 (1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-oneoxime Example 1A (E)-ethyl 3-(4-fluorophenyl)-2-methylacrylate

4-Fluorobenzaldehyde (12 g, 97 mmol) was dissolved in toluene (500 mL).(Carboethoxyethylidene)triphenylphosphorane (42 g, 116 mmol) was addedand the mixture was heated to reflux until the starting material wasconsumed. The solution was cooled, diluted with hexanes, and the solidwas filtered. The filtrate was evaporated in vacuo. The remainingresidue was dissolved in ether, and filtered through a plug of silicagel using ether as eluent. The solvents were evaporated in vacuo toafford the title compound (20 g, 99% yield) as a yellow solid. ¹H NMR(DMSO-d₆) δ ppm: 7.64 (s, 1H), 7.38 (dd, J=8.65, 5.59 Hz, 2H), 7.08 (t,J=8.65 Hz, 2H), 4.27 (q, J=7.12 Hz, 2H), 2.10 (d, J=1.36 Hz, 3H),1.27-1.38 (m, 3H). MS (DCI⁺) 209 (M+H).

Example 1B (E)-3-(4-fluorophenyl)-2-methylacrylic acid

Example 1A (20 g, 0.1 mol) was dissolved in THF (400 mL) and 1M aq LiOH(200 mL) was added. The mixture was stirred at ambient temperatureovernight. The homogeneous solution was diluted with water, andextracted with ethyl acetate. The organic phase was washed with waterand brine, dried over Na₂SO₄, filtered and evaporated in vacuo to affordthe title compound (16.1 g, 89% yield) as a white solid. ¹H NMR (300MHz, CDCl₃) δ ppm 7.78 (s, 1H), 7.43 (dd, J=8.82, 5.42 Hz, 2H), 7.11 (t,J=8.65 Hz, 2H), 2.14 (s, 3H). MS (DCI⁺) 198 (M+NH₄).

Example 1C (E)-3-(4-fluorophenyl)-N-methoxy-N,2-dimethylacrylamide

Method A

A mixture of Example 1B (16.1 g, 89.4 mmol), N,O-dimethylhydroxylaminehydrochloride (9.15 g, 93.9 mmol), 1-hydroxybenzotriazole hydrate (12.7g, 93.9 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (17.9 g, 93.9 mmol), and diisopropylethyl amine (47.4 g,370 mmol) was stirred in DMF (400 mL) at ambient temperature overnight.The solution was diluted with water and extracted with ethyl acetate.The organic phase was washed with saturated sodium bicarbonate solution,1N HCl, water, brine, dried over Na₂SO₄, and evaporated in vacuo. Theresulting material was chromatographed (SiO₂, 20% ethyl acetate/hexanesto 50% ethyl acetate/hexanes) to yield the title compound (16.89 g, 58%yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.33 (dd, J=8.82,5.43 Hz, 2H), 7.00-7.14 (m, 2H), 6.79 (s, 1H), 3.70 (s, 3H), 3.29 (s,3H), 2.11 (s, 3H). MS (DCI⁺) 224 (M+H).

Method B

A solution of isopropylmagnesium chloride (2.0 M in THF, 59.1 mL, 118mmol) was added dropwise via addition funnel to a mixture of Example 1A(5.47 g, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.12 g,52.5 mmol) in THF (100 mL) at 0° C. Upon complete addition, the reactionwas allowed to proceed 2 hr at 0° C. The reaction was quenched by slowaddition of saturated aq NH₄Cl solution (70 mL). The mixture was stirred60 min, then partitioned between EtOAc (50 mL) and H₂O (100 mL). Theseparated aqueous phase was extracted with EtOAc, and the combinedorganic layer was washed with 1 N aq HCl and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude product was purified bychromatography on silica gel (Analogix® Intelliflash 280; SF65-400 gcolumn; 20% to 60% EtOAc/hexanes; 0-40 min) to give the title compound(5.06 g, 22.7 mmol, 86% yield) as a colorless oil. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 7.50-7.40 (m, 2H), 7.29-7.18 (m, 2H), 6.72 (s, 1H), 3.65(s, 3H), 3.19 (s, 3H), 2.01 (d, J=1.5 Hz, 3H). MS (DCI⁺) 224 (M+H).

Example 1D (E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one

Example 1C (7 g, 31.4 mmol) was dissolved in tetrahydrofuran (175 mL)and cooled to about −20° C. Ethylmagnesium bromide (1M in THF, 94 mL, 94mmol) was added dropwise. The solution was stirred while warming toabout 0° C. for 3 hr. The reaction was quenched with saturated NH₄Clsolution, and then diluted with water. The mixture was extracted withethyl acetate. The combined organic phase was washed with water andbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. The solidwas chromatographed (SiO₂, 10% ethyl acetate/hexanes) to afford thetitle compound as a yellow solid (4.59 g, 76% yield). ¹H NMR (300 MHz,CDCl₃) δ ppm 7.48 (s, 1H), 7.40 (dd, J=8.82, 5.43 Hz, 2H), 7.10 (t,J=8.65 Hz, 2H), 2.83 (q, J=7.12 Hz, 2H), 2.05 (d, J=1.36 Hz, 3H), 1.17(t, J=7.29 Hz, 3H). MS (DCI⁺) 193 (M+H).

Example 1E (1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one oxime

Example 1D (4.59 g, 23.9 mmol) was dissolved in pyridine (100 mL),followed by addition of hydroxylamine hydrochloride (2.5 g, 35.8 mmol).The reaction was stirred at ambient temperature for two hours. Thesolvent was evaporated in vacuo and the residue partitioned between 1NHCl and ethyl acetate. The organic phase was washed with water andbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. Theresulting solid was chromatographed (SiO₂, 20% ethyl acetate/hexanes),and then recrystallized from hexanes to afford the title compound (3.25grams, 66% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.69 (bs, 1H),7.33-7.24 (m, 2H), 7.11-7.01 (m, 2H), 6.87 (s, 1H), 2.70 (q, J=7.6 Hz,2H), 2.04 (d, J=1.2 Hz, 3H), 1.18 (t, J=7.6 Hz, 3H). MS (DCI⁺) 208(M+H).

Example 2 (1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-oneO-methyloxime

Example 1D (100 mg, 0.52 mmol) was dissolved in pyridine (5 mL),followed by addition of methoxylamine hydrochloride (65 mg, 0.78 mmol),and the reaction was stirred at ambient temperature overnight. Thesolvent was evaporated in vacuo and the residue partitioned between 1NHCl and ethyl acetate. The organic phase was washed with water andbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. Theresulting solid was chromatographed (SiO₂, 20% ethyl acetate/hexanes) toafford the title compound (42 mg, 37% yield). ¹H NMR (300 MHz, CDCl₃) δppm 7.25-7.31 (m, 2H), 7.04 (t, 2H), 6.80 (s, 1H), 3.94 (s, 3H), 2.61(q, J=7.46 Hz, 2H), 2.04 (d, J=1.36 Hz, 3H), 1.11 (t, J=7.46 Hz, 3H). MS(ESI⁺) 221 (M+H).

Example 3 (1E,3E)-1-(2-fluorophenyl)-2-methylpent-1-en-3-one oximeExample 3A (E)-ethyl 3-(2-fluorophenyl)-2-methylacrylate

2-Fluorobenzaldehyde (5.0 g, 40.3 mmol) was dissolved in 150 mL toluene.(Carboethoxyethylidene)triphenylphosphorane (42 g; 116 mmol) was addedand the mixture was heated to reflux overnight. The solution was cooled,diluted with hexanes, and the solid was filtered. The filtrate wasevaporated in vacuo, then dissolved in ether and filtered through a plugof silica gel using ether as eluent. The solvents were evaporated invacuo to afford the title compound (10.57 g) as a yellow solid. ¹H NMR(300 MHz, CDCl₃) δ ppm 7.70 (s, 1H), 7.26-7.38 (m, 3H), 7.17 (m, 2H),4.28 (q, J=7.12 Hz, 2H), 2.04 (s, 3H), 1.35 (t, J=7.12 Hz, 3H).

Example 3B (E)-3-(2-fluorophenyl)-N-methoxy-N,2-dimethylacrylamide

N,O-dimethylhydroxylamine hydrochloride (7 g, 72 mmol) was slurried inCH₂Cl₂ (250 mL) and cooled to 0-5° C. A solution of trimethylaluminum(2M in toluene, 36 mL, 72 mmol) was added dropwise. The mixture waswarmed to ambient temperature and stirred for 1 hr. A solution ofExample 3A (5 g, 24.0 mmol) in CH₂Cl₂ (100 ml) was added and thesolution was heated to reflux overnight. The reaction mixture was cooledin an ice bath and quenched carefully with ice cold 0.5 M HCl. Themixture was filtered through celite filter aid and extracted withCH₂Cl₂. The organic phase was washed with water and brine, dried overNa₂SO₄, filtered, and evaporated in vacuo. The crude product waschromatographed (SiO₂, 100% hexanes to 20% ethyl acetate/hexanes) toafford the title compound (1.88 g, 35% yield) as a light yellow oil. ¹HNMR (300 MHz, CDCl₃) δ ppm 7.27-7.38 (m, 2H), 7.04-7.17 (m, 2H), 6.79(s, 1H), 3.72 (s, 3H), 3.30 (s, 3H), 2.04 (s, 3H). MS (ESI⁺) 224 (M+H).

Example 3C (E)-1-(2-fluorophenyl)-2-methylpent-1-en-3-one

Example 3B (870 mg, 3.91 mmol) was dissolved in tetrahydrofuran (20 mL)and cooled to about −20° C. Ethylmagnesium bromide (1M in THF, 7.8 mL,7.8 mmol) was added dropwise, and the reaction was stirred for 1.5 hr atabout −20° C. The reaction was quenched with NH₄Cl solution andextracted with ethyl acetate. The combined organic extract was washedwith water and brine, dried over Na₂SO₄, filtered, and evaporated invacuo. The resulting oil was chromatographed (SiO₂, 10% ethylacetate/hexanes) to afford the title compound as a yellow oil (240 mg,32% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.55 (s, 1H), 7.29-7.41 (m,2H), 7.05-7.20 (m, 3H), 2.85 (q, J=7.46 Hz, 2H), 1.18 (q, J=7.46 Hz,3H). MS (DCI⁺) 193 (M+H).

Example 3D (1E,3E)-1-(2-fluorophenyl)-2-methylpent-1-en-3-one oxime

Example 3C (100 mg, 0.52 mmol) was dissolved in pyridine (3 mL),followed by addition of hydroxylamine hydrochloride (78 mg, 1.12 mmol).The solution was stirred at ambient temperature for 1.5 hr. The solventwas evaporated in vacuo and the residue partitioned between 1N HCl andethyl acetate. The organic phase was washed with water and brine, driedover Na₂SO₄, filtered, and evaporated in vacuo. The resulting solid wasrecrystallized from hexanes to afford the title compound (52 mg, 48%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.27-7.34 (m, 2H), 7.04-7.17 (m,2H), 6.89 (s, 1H), 2.72 (q, J=7.46 Hz, 2H), 1.99 (s, 3H), 1.18 (t,J=7.63 Hz, 3H). MS (DCI⁺) 208 (M+H).

Example 4 (1E,3E)-1-(4-fluorophenyl)-2-methylhex-1-en-3-one oximeExample 4A (E)-1-(4-fluorophenyl)-2-methylhex-1-en-3-one

Example 1C (2 g, 8.95 mmol) was dissolved in tetrahydrofuran (50 mL) andcooled to about −20° C. Propylmagnesium chloride (2M in Et₂O, 9 mL, 18mmol) was added dropwise and the resulting mixture was stirred at about−20° C. for 1 hr. The solution was quenched with saturated NH₄Clsolution and extracted with ethyl acetate. The combined organic phasewas washed with water and brine, dried over Na₂SO₄, filtered, andevaporated in vacuo. The resulting material was chromatographed (SiO₂,10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to afford thetitle compound (900 mg, 49% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.47(s, 1H), 7.36-7.43 (m, 2H), 7.06-7.14 (m, 2H), 2.77 (q, J=7.29 Hz, 2H),2.04 (d, J=1.36 Hz, 3H), 1.65-1.78 (m, 2H), 0.98 (t, J=7.29 Hz, 3H). MS(DCI⁺) 207 (M+H).

Example 4B (1E,3E)-1-(4-fluorophenyl)-2-methylhex-1-en-3-one oxime

Example 4A (200 mg, 0.97 mmol) was dissolved in pyridine (3 mL),followed by addition of hydroxylamine hydrochloride (101 mg, 1.45 mmol).After stirring at ambient temperature for 2 hr, the solvent wasevaporated in vacuo and the residue partitioned between 1N HCl and ethylacetate. The organic phase was washed with water and brine, dried overNa₂SO₄, filtered, and evaporated in vacuo. The resulting solid wasrecrystallized from hexanes to afford the title compound (78 mg, 36%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.25-7.31 (m, 2H), 7.05 (m, 2H),6.85 (s, 1H), 2.61-2.69 (m, 2H), 2.02 (s, 3H), 1.54-1.68 (m, 2H), 1.02(t, J=7.29 Hz, 3H).

Example 5 (1E,3E)-1-(4-fluorophenyl)-2,4,4-trimethylpent-1-en-3-oneoxime Example 5A (E)-1-(4-fluorophenyl)-2,4,4-trimethylpent-1-en-3-one

Example 1C (2 g, 8.95 mmol) was dissolved in tetrahydrofuran (50 mL) andcooled to about −20° C. tert-Butylmagnesium chloride (1M in THF, 18 mL,18 mmol) was added dropwise. After stirring at about −20° C. for 1 hr,the reaction was quenched with saturated NH₄Cl solution and extractedwith ethyl acetate. The organic phase was washed with water and brine,dried over Na₂SO₄, filtered, and evaporated in vacuo. The resultingmaterial was chromatographed (SiO₂, 10% ethyl acetate/hexanes to 50%ethyl acetate/hexanes) to afford the title compound (410 mg, 21% yield).¹H NMR (300 MHz, CDCl₃) δ ppm 7.25-7.33 (m, 2H), 7.06 (m, 2H), 6.82 (s,1H), 2.03 (d, J=1.70 Hz, 3H), 1.31 (s, 9H). MS (DCI⁺) 221 (M+H).

Example 5B (1E,3E)-1-(4-fluorophenyl)-2,4,4-trimethylpent-1-en-3-oneoxime

Example 5A (200 mg, 0.91 mmol) was dissolved in pyridine (3 mL),followed by addition of hydroxylamine hydrochloride (101 mg, 1.45 mmol).The solution was stirred at ambient temperature overnight. The solventwas evaporated in vacuo and the residue partitioned between 1N HCl andethyl acetate. The organic phase was washed with water and brine, driedover Na₂SO₄, filtered, and evaporated in vacuo. The resulting solid wasrecrystallized from hexanes to afford the title compound (92 mg, 43%yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.31 (m, 2H), 7.04 (m, 2H), 6.18(s, 1H), 2.03 (d, J=1.36 Hz, 3H), 1.22 (s, 9H).

Example 6 (1E,3E)-1-(4-fluorophenyl)-2-methylhept-1-en-3-one oximeExample 6A (E)-1-(4-fluorophenyl)-2-methylhept-1-en-3-one

Example 1C (2 g, 8.96 mmol) was dissolved in tetrahydrofuran (50 mL) andcooled to about −20° C. Butylmagnesium chloride (2M in Et₂O, 8.96 mL,17.9 mmol) was added dropwise and the mixture was stirred at about −20°C. for 1 hr. The reaction was quenched with saturated NH₄Cl solution andextracted with ethyl acetate. The combined organic extract was washedwith water and brine, dried over Na₂SO₄, filtered, and evaporated invacuo. The resulting material was chromatographed (SiO₂, 10% ethylacetate/hexanes to 50% ethyl acetate/hexanes) to afford the titlecompound (1.2 g, 61% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.46 (s, 1H),7.36-7.43 (m, 2H), 7.07-7.14 (m, 2H), 2.76-2.81 (m, 2H), 2.04 (d, J=1.36Hz, 3H), 1.66 (dt, J=15.17, 7.50 Hz, 2H), 1.32-1.45 (m, 2H), 0.95 (t,J=7.29 Hz, 3H). MS (DCI⁺) 221 (M+H).

Example 6B (1E,3E)-1-(4-fluorophenyl)-2-methylhept-1-en-3-one oxime

Example 6A (250 mg, 1.14 mmol) was dissolved in pyridine (5 mL),followed by addition of hydroxylamine hydrochloride (119 mg, 1.70 mmol).The resulting mixture was stirred at ambient temperature for two hours.The solvent was evaporated in vacuo and the residue partitioned between1N HCl and ethyl acetate. The organic phase was washed with water andbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. Theresulting solid was chromatographed (SiO₂, 20% ethyl acetate/hexanes),then recrystallized from hexanes to afford the title compound as a whitesolid (110 mg, 38% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.25-7.31 (m,2H), 7.01-7.10 (m, 2H), 6.84 (s, 1H), 2.63-2.70 (m, 2H), 2.02 (s, 3H),1.49-1.58 (m, 2H), 1.39-1.47 (m, 2H), 0.96 (t, J=7.29 Hz, 3H).

Example 7 (1E,3Z)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oximeExample 7A (E)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one

Example 1C (2 g, 8.96 mmol) was dissolved in tetrahydrofuran (50 mL) andcooled to about −20° C. Isopropylmagnesium bromide (2M in THF, 8.96 mL,17.9 mmol) was added dropwise, and the resulting mixture was stirredwhile warming to 0° C. for 2.5 hr. The reaction was quenched withsaturated NH₄Cl solution and diluted with water. The mixture wasextracted with ethyl acetate. The combined organic extract was washedwith water and brine, dried over Na₂SO₄, filtered, and evaporated invacuo. The solid was chromatographed (SiO₂, 10% ethyl acetate/hexanes)to afford the title compound as a yellow solid (590 mg, 32% yield). ¹HNMR (300 MHz, CDCl₃) δ ppm 7.46 (s, 1H), 7.37-7.43 (m, 3H), 7.10 (m,2H), 3.38-3.51 (m, 1H), 2.05 (d, J=1.36 Hz, 3H), 1.18 (s, 3H), 1.16 (s,3H).

Example 7B (1E,3Z)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime

Example 7A (250 mg, 1.21 mmol) was dissolved in pyridine (3 mL),followed by addition of hydroxylamine hydrochloride (101 mg, 1.45 mmol).The reaction was stirred at ambient temperature overnight. The solventwas evaporated in vacuo and the residue partitioned between 1N HCl andethyl acetate. The organic phase was washed with water and brine, driedover Na₂SO₄, filtered, and evaporated in vacuo. The resulting solid waschromatographed using 10% ethyl acetate/hexanes, and the earlier elutingcomponent was isolated to yield the title compound (62 mg, 23% yield).¹H NMR (300 MHz, CDCl₃) δ ppm 7.27-7.33 (m, 2H), 6.99-7.08 (m, 2H), 6.61(s, 1H), 3.39 (m, 1H), 2.02 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H).

Example 8 (1E,3E)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime

Example 7A (250 mg, 1.21 mmol) was dissolved in pyridine (3 mL),followed by addition of hydroxylamine hydrochloride (101 mg, 1.45 mmol).The reaction was stirred at ambient temperature overnight. The solventwas evaporated in vacuo and the residue partitioned between 1N HCl andethyl acetate. The organic phase was washed with water and brine, driedover Na₂SO₄, filtered, and evaporated in vacuo. The resulting solid waschromatographed using 10% ethyl acetate/hexanes, and the later elutingcomponent was isolated to yield the title compound (67 mg, 25% yield).¹H NMR (300 MHz, CDCl₃) δ ppm 7.27-7.33 (m, 2H), 7.00-7.07 (m, 2H), 7.04(s, 1H), 6.30 (s, 1H), 2.70 (m, 1H), 2.06 (s, 3H), 1.19 (s, 3H), 1.17(s, 3H).

Example 9 (1E,3E)-1-(3-chloro-4-fluorophenyl)-2-methylpent-1-en-3-oneoxime Example 9A (E)-ethyl 3-(3-chloro-4-fluorophenyl)-2-methylacrylate

3-Chloro-4-fluorobenzaldehyde (10 g, 63.1 mmol) was dissolved in 300 mLtoluene. (Carboethoxyethylidene)triphenylphosphorane (25 g, 69.4 mmol)was added and the mixture was heated to reflux overnight. The solutionwas cooled, diluted with hexanes and the solid was filtered. Thefiltrate was evaporated in vacuo, and the residue was dissolved in etherand filtered through a plug of silica using ether as eluent. The solventwas evaporated in vacuo to afford the title compound (15.55 g) as a semisolid. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.56 (s, 1H), 7.44 (m, 1H),7.23-7.32 (m, 1H), 7.16 (m, 1H), 4.28 (q, J=7.12 Hz, 2H), 2.09 (d,J=1.36 Hz, 3H), 1.35 (t, J=7.36 Hz, 3H). MS (DCI⁺) 243 (M+H).

Example 9B (E)-3-(3-chloro-4-fluorophenyl)-2-methylacrylic acid

Example 9A (15.5 g, 63.9 mmol) was dissolved in tetrahydrofuran (300 mL)and 1M LiOH (128 mL) was added. The mixture was stirred at ambienttemperature overnight. The homogeneous solution was diluted with waterand extracted with ethyl acetate. The organic phase was washed withwater and brine, dried over Na₂SO₄, filtered, and evaporated in vacuo toafford the title compound (12 g, 88% yield) as an off-white solid. ¹HNMR (300 MHz, CDCl₃) δ ppm 7.70 (s, 1H), 7.48 (dd, J=7.12, 2.37 Hz, 1H),7.27-7.33 (m, 1H), 7.19 (t, J=8.65 Hz, 1H), 2.12 (s, 3H).

Example 9C(E)-3-(3-chloro-4-fluorophenyl)-N-methoxy-N,2-dimethylacrylamide

A mixture of Example 9B (11.9 g, 55.45 mmol), N,O-dimethylhydroxylaminehydrochloride (5.7 g, 58 mmol), 1-hydroxybenzotriazole hydrate (7.88 g,53.8 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (11 g, 57.58 mmol) and diisopropylethyl amine (47.4 g,63.9 mL, 370 mol) was stirred in DMF (400 mL) at ambient temperatureovernight. The solution was diluted with water and extracted with ethylacetate. The combined organic extract was washed with saturated sodiumbicarbonate solution, 1N HCl, water, brine, dried over Na₂SO₄, filtered,and evaporated in vacuo. The resulting material was chromatographed(SiO₂, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to leavethe title compound (6.85 g, 48% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm7.39 (dd, J=7.12, 2.37 Hz, 1H), 7.10-7.21 (m, 2H), 6.71 (s, 1H), 3.69(s, 3H), 3.28 (s, 3H), 2.10 (s, 3H). MS (DCI⁺) 258 (M+H).

Example 9D (E)-1-(3-chloro-4-fluorophenyl)-2-methylpent-1-en-3-one

Example 9C (2 g, 7.76 mmol) was dissolved in tetrahydrofuran (50 mL) andcooled to about −20° C. Ethylmagnesium bromide (1M in THF, 15.5 mL, 15.5mmol) was added dropwise and the resulting mixture was stirred at about−20° C. for 1 hr. The reaction was quenched with saturated NH₄Clsolution and extracted with ethyl acetate. The organic phase was washedwith water and brine, dried over Na₂SO₄, filtered, and evaporated invacuo. The resulting material was chromatographed (SiO₂, 10% ethylacetate/hexanes to 50% ethyl acetate/hexanes) to afford the titlecompound (930 mg, 53% yield) as a yellow waxy solid. ¹H NMR (300 MHz,CDCl₃) δ ppm 7.45 (dd, J=6.95, 2.20 Hz, 1H), 7.39 (s, 1H), 7.20-7.30 (m,1H), 7.18 (t, J=8.65 Hz, 1H), 2.81 (q, J=7.23 Hz, 2H), 2.04 (d, J=1.36Hz, 3H), 1.17 (t, J=7.29 Hz, 3H). MS (DCI⁺) 227 (M+H).

Example 9E (1E,3E)-1-(3-chloro-4-fluorophenyl)-2-methylpent-1-en-3-oneoxime

Example 9D (400 mg, 1.76 mmol) was dissolved in pyridine (5 mL),followed by addition of hydroxylamine hydrochloride (184 mg, 2.65 mmol).The resulting mixture was stirred at ambient temperature two hours. Thesolvent was evaporated in vacuo and the residue partitioned between 1NHCl and ethyl acetate. The organic phase was washed with water andbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. Theresulting solid was chromatographed (SiO₂, 20% ethyl acetate/hexanes),then recrystallized from hexanes to afford the title compound as a whitesolid (221 mg, 52% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm 7.36 (dd,J=6.95, 1.86 Hz, 1H), 7.10-7.21 (m, 3H), 6.79 (s, 2H), 2.68 (q, J=7.80Hz, 2H), 2.03 (s, 1H), 1.16 (t, J=7.63 Hz, 3H).

Example 10 (1E,3Z)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one oxime

To a solution of Example 1D (1.96 g, 10.2 mmol) in pyridine (40 mL) wasadded hydroxylamine hydrochloride (1.06 g, 15.3 mmol) in one portion.The reaction was stirred at ambient temperature for 12 hr, and thenconcentrated in vacuo. The residue was partitioned between EtOAc and 1Maq HCl. The separated organic phase was washed with 1M aq HCl and brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude productwas purified by chromatography on silica gel (Analogix Intelliflash 280;5% to 30% EtOAc/hexanes; SF40-115 g column) and the late elutingcomponent was isolated to afford the title compound as a white solid(0.16 g, 7.6% yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.34 (s, 1H),7.44-7.34 (m, 2H), 7.25-7.15 (m, 2H), 6.36 (s, 1H), 2.36 (q, J=7.4 Hz,2H), 1.98 (d, J=1.5 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H). MS (DCI⁺): 208(M+H).

Example 11 (2E,3E)-4-(4-fluorophenyl)but-3-en-2-one oxime Example 11A(E)-methyl 3-(4-fluorophenyl)acrylate

A mixture of 1-bromo-4-fluorobenzene (10 g, 57 mmol), methyl acrylate(4.5 g, 52 mmol), tetraethylammonium chloride (8.6 g, 52 mmol),N-cyclohexyl-N-methylcyclohexanamine (15 g, 78 mmol), and palladium (II)acetate (0.35 g, 1.6 mmol) in dimethylacetamide (200 mL) was heated to100° C. under an argon atmosphere. The reaction was allowed to proceeduntil the aryl halide was consumed. The reaction mixture was then cooledto room temperature, diluted with Et₂O, and washed three times withwater. The separated organic phase was dried over MgSO₄ and concentratedin vacuo. The crude product was purified by flash column chromatographyon silica gel eluting with EtOAc/hexanes to afford 8.5 g (91% yield) ofthe title compound.

Example 11B (E)-3-(4-fluorophenyl)-N-methoxy-N-methylacrylamide

The title compound was prepared according to the procedure of Example 1Cmethod B, substituting Example 11A for Example 1A.

Example 11C (E)-4-(4-fluorophenyl)but-3-en-2-one

The title compound was prepared according to the procedure of Example1D, substituting Example 11B for Example 1C and methylmagnesium bromidefor ethylmagnesium bromide.

Example 11D (2E,3E)-4-(4-fluorophenyl)but-3-en-2-one oxime

The title compound was prepared according to the procedure of Example1E, substituting Example 11C for Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δppm 11.13 (s, 1H), 7.61 (dd, J=8.7, 5.6 Hz, 2H), 7.18 (dd, J=12.2, 5.6Hz, 2H), 6.95 (d, J=16.6 Hz, 1H), 6.80 (d, J=16.6 Hz, 1H), 1.98 (s, 3H).MS (DCI⁺): 180 (M+H).

Example 12 (1E,3E)-1-(4-fluorophenyl)hex-1-en-3-one oxime Example 12A(E)-1-(4-fluorophenyl)hex-1-en-3-one

The title compound was prepared according to the procedure of Example1D, substituting Example 11B for Example 1C and propylmagnesium bromidefor ethylmagnesium bromide.

Example 12B (1E,3E)-1-(4-fluorophenyl)hex-1-en-3-one oxime

The title compound was prepared according to the procedure of Example1E, substituting Example 12A for Example 1D. ¹H NMR (500 MHz, DMSO/D₂O)δ ppm 7.61 (dd, J=8.7, 5.6 Hz, 2H), 7.22-7.15 (m, 2H), 6.95 (d, J=16.7Hz, 1H), 6.72 (d, J=16.6 Hz, 1H), 2.55-2.49 (m, 2H), 1.55-1.44 (m, 2H),0.94 (t, J=7.1 Hz, 3H). MS (ESI⁻): 208 (M+H).

Example 13 (1E,3E)-1-(4-fluorophenyl)pent-1-en-3-one oxime and(1E,3E)-1-(4-fluorophenyl)pent-1-en-3-one oxime, about 1:1 mixtureExample 13A (E)-1-(4-fluorophenyl)pent-1-en-3-one

The title compound was prepared according to the procedure of Example1D, substituting Example 11B for Example 1C.

Example 13B (1E,3E)-1-(4-fluorophenyl)pent-1-en-3-one oxime and(1E,3Z)-1-(4-fluorophenyl)pent-1-en-3-one oxime, about 1:1 mixture

The title compound was prepared according to the procedure of Example1E, substituting Example 13A for Example 1D. Data for the mixtureobtained: ¹H NMR (500 MHz, DMSO/D₂O) δ ppm 7.67-7.59 (m, 3H), 7.36-7.30(m, 2H), 7.25-7.16 (m, 4H), 7.04 (d, J=16.9 Hz, 1H), 6.96 (d, J=16.7 Hz,1H), 6.69 (d, J=16.7 Hz, 1H), 2.56-2.45 (m, 4H), 1.11 (t, J=7.5 Hz, 3H),1.04 (t, J=7.5 Hz, 3H). MS (ESI⁺): 176 (M−17).

Example 14 (1E,3E)-1-(3,4-difluorophenyl)-2-methylpent-1-en-3-one oxime

The title compound was prepared according to the procedure of Example 1,substituting 3,4-difluorobenzaldehyde for 4-fluorobenzaldehyde. ¹H NMR(300 MHz, CDCl₃) δ ppm 8.14 (bs, 1H), 7.21-7.09 (m, 2H), 7.07-6.98 (m,1H), 6.80 (s, 1H), 2.68 (q, J=7.6 Hz, 2H), 2.03 (d, J=1.3 Hz, 3H), 1.16(t, J=7.6 Hz, 3H). MS (DCI⁺): 226 (M+H).

Example 15 (1E,3E)-2-methyl-1-(3,4,5-trifluorophenyl)pent-1-en-3-oneoxime

The title compound was prepared according to the procedure of Example 1,substituting 3,4,5-trifluorobenzaldehyde for 4-fluorobenzaldehyde. ¹HNMR (300 MHz, CDCl₃) δ ppm 8.00 (bs, 1H), 6.97-6.88 (m, 2H), 6.72 (s,1H), 2.66 (q, J=7.6 Hz, 2H), 2.03 (d, J=1.3 Hz, 3H), 1.15 (t, J=7.6 Hz,3H). MS (DCI⁺): 244 (M+H).

Example 16 (1E,3E)-1-(4-fluorophenyl)hept-1-en-3-one oxime Example 16A(E)-1-(4-fluorophenyl)hept-1-en-3-one

The title compound was prepared according to the procedure of Example1D, substituting Example 11B for Example 1C and butylmagnesium bromidefor ethylmagnesium bromide.

Example 16B (1E,3E)-1-(4-fluorophenyl)hept-1-en-3-one oxime

The title compound was prepared according to the procedure of Example1E, substituting Example 16A for Example 1D. ¹H NMR (500 MHz, DMSO/D₂O)δ ppm 7.61 (dd, J=8.7, 5.6 Hz, 2H), 7.22-7.16 (m, 2H), 6.94 (d, J=16.7Hz, 1H), 6.71 (d, J=16.6 Hz, 1H), 2.58-2.50 (m, 2H), 1.49-1.40 (m, 2H),1.40-1.30 (m, 2H), 0.90 (t, J=7.6 Hz, 3H). MS (ESI⁺): 222 (M+H).

Example 17 (1E,3E)-1-(4-fluoro-3-methylphenyl)-2-methylpent-1-en-3-oneoxime

The title compound was prepared according to the procedure of Example 1,substituting 4-fluoro-3-methylbenzaldehyde for 4-fluorobenzaldehyde. ¹HNMR (300 MHz, CDCl₃) δ ppm 8.06 (bs, 1H), 7.17-7.07 (m, 2H), 7.03-6.94(m, 1H), 6.83 (s, 1), 2.69 (q, J=7.6, 2H), 2.29 (d, J=2.0, 3H), 2.03 (d,J=1.3, 3H), 1.17 (t, J=7.6, 3H). MS (DCI⁺): 222 (M+H).

Example 18(1E,3E)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-2-methylpent-1-en-3-oneoxime

The title compound was prepared according to the procedure of Example 1,substituting 4-fluoro-3-(trifluoromethyl)benzaldehyde for4-fluorobenzaldehyde. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.86 (s, 1H),7.58-7.43 (m, 2H), 7.24-7.15 (m, 1H), 6.84 (s, 1H), 2.69 (q, J=7.6 Hz,2H), 2.02 (d, J=1.3 Hz, 3H), 1.17 (t, J=7.6 Hz, 3H). MS (DCI⁺): 276(M+H).

Example 192-fluoro-5-[(1E,3E)-3-(hydroxyimino)-2-methylpent-1-enyl]benzonitrile

The title compound was prepared according to the procedure of Example 1,substituting 2-fluoro-5-formylbenzonitrile for 4-fluorobenzaldehyde. ¹HNMR (300 MHz, CDCl₃) δ ppm 8.03 (bs, 1H), 7.59-7.48 (m, 2H), 7.22 (t,J=8.6 Hz, 1H), 6.78 (s, 1H), 2.68 (q, J=7.6 Hz, 2H), 2.01 (d, J=1.3 Hz,3H), 1.16 (t, J=7.6 Hz, 3H). MS (DCI⁺): 223 (M+H).

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

The invention claimed is:
 1. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof

wherein R¹ represent substituents of the phenyl group and each R¹ isindependently alkyl, alkenyl, alkynyl, —CN, halogen, —OR^(a), —NO₂,—N(R^(a))(R^(b)), —N(R^(b))C(O)R^(a), —N(R^(b))S(O)₂R^(1a),—N(R^(b))C(O)OR^(a), —N(R^(b))C(O)N(R^(a))(R^(b)),—N(R^(b))S(O)₂N(R^(a))(R^(b)), —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))(R^(b)), —SR^(a), —SF₅, —S(O)R^(1a), —S(O)₂R^(1a),—S(O)₂OR^(1a), —S(O)₂N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—CN, haloalkyl,—(CR^(d)R^(e))_(q)—OR^(a), —(CR^(d)R^(e))_(q)—NO₂,—(CR^(d)R^(e))_(q)—N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂R^(1a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)OR^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—C(O)R^(a), —(CR^(d)R^(e))—C(O)OR^(a),—(CR^(d)R^(e))_(q)—C(O)N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—S(O)₂R^(1a),—(CR^(d)R^(e))_(q)—S(O)₂OR^(1a), or—(CR^(d)R^(e))_(q)—S(O)₂N(R^(a))(R^(b)); R² is C₁₋₆ alkyl or haloalkyl;R³ is C₂₋₆ alkyl; Y is —OH, —O(C₁₋₄ alkyl), —N(R^(f))(R^(g)),—N(R^(f))C(O)R^(g), —N(R^(f))S(O)₂R^(g), or—N(R^(f))C(O)N(R^(f))(R^(g)); R^(a) and R^(b), at each occurrence, areeach independently hydrogen, alkyl, or haloalkyl; R^(1a), at eachoccurrence, is independently alkyl or haloalkyl; R^(d) and R^(e), ateach occurrence, are each independently hydrogen, alkyl, halogen, orhaloalkyl; R^(f) and R^(g), at each occurrence, are each independentlyhydrogen, alkyl, or haloalkyl; m is 1, 2, 3, 4, or 5; and q is 1, 2, 3,or 4; with the proviso that the compound is not(Z)-4-(4-chlorophenyl)-3-methylbut-3-en-2-oxime or(E)-4-(4-chlorophenyl)-3-methylbut-3-en-2-oxime; and a pharmaceuticallyacceptable carrier.
 2. The pharmaceutical composition of claim 1 furthercomprising one or more second pain reducing agent.
 3. A compound that is(1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one O-methyloxime;(1E,3E)-1-(2-fluorophenyl)-2-methylpent-1-en-3-one oxime;(1E,3E)-1-(4-fluorophenyl)-2-methylhex-1-en-3-one oxime;(1E,3E)-1-(4-fluorophenyl)-2,4,4-trimethylpent-1-en-3-one oxime;(1E,3E)-1-(4-fluorophenyl)-2-methylhept-1-en-3-one oxime;(1E,3Z)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime;(1E,3E)-1-(4-fluorophenyl)-2,4-dimethylpent-1-en-3-one oxime;(1E,3E)-1-(4-fluorophenyl)hex-1-en-3-one oxime;(1E,3E)-1-(3,4-difluorophenyl)-2-methylpent-1-en-3-one oxime; or(1E,3E)-2-methyl-1-(3,4,5-trifluorophenyl)pent-1-en-3-one oxime; or apharmaceutically acceptable salt thereof. 4.(1E,3E)-1-(4-fluorophenyl)-2-methylpent-1-en-3-one oxime or apharmaceutically acceptable salt thereof.